Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.

Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality.Objective: Our objective was to assess the impact of some...

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Fecha de publicación:
2020
Institución:
Universidad del Rosario
Repositorio:
Repositorio EdocUR - U. Rosario
Idioma:
eng
OAI Identifier:
oai:repository.urosario.edu.co:10336/24946
Acceso en línea:
https://doi.org/10.3389/fphar.2020.00555
https://repository.urosario.edu.co/handle/10336/24946
Palabra clave:
drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
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spelling 79733068600193318196005209482560005be2068-882c-4b73-8a37-71a88beffefa8a7926da-57e4-40d9-94cc-92bcf8030524e6e8a4e2-5ba7-496c-bdc7-8f8b94ad1b1c77997b14-6df8-446d-8325-69318a1c1db8cd6733a7-df78-4b48-961d-7c8190a7b74a79141398600797827702020-06-11T13:21:54Z2020-06-11T13:21:54Z2020Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality.Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy.Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology).Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients.Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.application/pdfhttps://doi.org/10.3389/fphar.2020.005551663-9812https://repository.urosario.edu.co/handle/10336/24946engFrontiers Media S.A.555555Frontiers in pharmacologyVol. 11Frontiers in pharmacology, ISSN:1663-9812, Vol.11, (2020); pp. 555-555Abierto (Texto Completo)http://purl.org/coar/access_right/c_abf2instname:Universidad del Rosarioreponame:Repositorio Institucional EdocURdrug resistant epilepsydrug-related side effects and adverse reactionspharmacogeneticspharmacovigilancephenytoinPossible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.articleArtículohttp://purl.org/coar/version/c_970fb48d4fbd8a85http://purl.org/coar/resource_type/c_6501Calderón Ospina, Carlos AlbertoRestrepo Fernández, Carlos MartínFonseca Mendoza, Dora JanethGalvez, Jubby MarcelaLopez-Cabra, ClaudiaMorales, NataliaRodriguez, JesusAristizabal-Gutierrez, Fabio AncizarVélez van Meerbeke, Alberto FranciscoLaissue, PaulORIGINALfphar-11-00555.pdfapplication/pdf339022https://repository.urosario.edu.co/bitstreams/069144f1-c455-43ed-9622-5dd188c6203f/downloadc66ce0d64f871178b6b7c876ff13413fMD51TEXTfphar-11-00555.pdf.txtfphar-11-00555.pdf.txtExtracted texttext/plain44202https://repository.urosario.edu.co/bitstreams/ea2a7310-d626-4397-b99a-e430cc27d66b/download550419a15964a9c90f9cc7ab294bdfa0MD52THUMBNAILfphar-11-00555.pdf.jpgfphar-11-00555.pdf.jpgGenerated Thumbnailimage/jpeg4251https://repository.urosario.edu.co/bitstreams/d2073f4a-4ca1-49da-95d4-3408c6d11679/downloaddb0e59ea8448b3ae7810e996cf4c23f5MD5310336/24946oai:repository.urosario.edu.co:10336/249462021-11-07 08:25:43.408https://repository.urosario.edu.coRepositorio institucional EdocURedocur@urosario.edu.co
dc.title.spa.fl_str_mv Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
title Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
spellingShingle Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
title_short Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
title_full Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
title_fullStr Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
title_full_unstemmed Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
title_sort Possible Genetic Determinants of Response to Phenytoin in a Group of Colombian Patients With Epilepsy.
dc.subject.keyword.spa.fl_str_mv drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
topic drug resistant epilepsy
drug-related side effects and adverse reactions
pharmacogenetics
pharmacovigilance
phenytoin
description Background: Epilepsy is a serious health problem worldwide. Despite the introduction of new antiepileptic drugs (AEDs) almost 30% of these patients have drug-resistant forms of the disease (DRE), with a significant increase in morbi-mortality.Objective: Our objective was to assess the impact of some genetic factors and its possible association with treatment response and adverse drug reactions (ADRs) to phenytoin in 67 adult Colombian patients with epilepsy.Methods: We conducted an analytical, observational, prospective cohort study to screen four polymorphisms in pharmacogenes: CYP2C9*2-c.430C>T (rs1799853), CYP2C9*3-c.1075A>C (rs1057910), ABCB1-c.3435T>C (rs1045642), and SCN1A-IVS5-91G>A (rs3812718), and their association with treatment response. Patients were followed for 1 year to confirm the existence of DRE (non-response) and ADRs using an active pharmacovigilance approach, followed by a consensus in order to classify ADRs according to causality, preventability, intensity and their relation with phenytoin dose, the duration of treatment, and susceptibility factors (DoTS methodology).Results: A little more than half of evaluated subjects (52.2%) were non-responding to phenytoin. Regarding the genotype-phenotype correlation there was no association between polymorphisms of SCN1A and ABCB1 and DRE (non-response) (p = 0.34), and neither with CYP2C9 polymorphisms and the occurrence of ADRs (p = 0.42). We only found an association between polymorphic alleles of CYP2C9 and vestibular-cerebellar ADRs (dizziness, ataxia, diplopia, and dysarthria) (p = 0.001). Alleles CYP2C9*2-c.430C>T and CYP2C9*3-c.1075A>C were identified as susceptibility factors to ADRs in 24% of patients.Conclusions: Decreased function alleles of CYP2C9 were highly predictive of vestibular-cerebellar ADRs to phenytoin in our study (p = 0.001). However, the genetic variants CYP2C9*2-c.430C>T, CYP2C9*3-c.1075A>C, ABCB1-c.3435T>C, and SCN1A-IVS5-91G>A, were not associated with treatment response in our study.
publishDate 2020
dc.date.accessioned.none.fl_str_mv 2020-06-11T13:21:54Z
dc.date.available.none.fl_str_mv 2020-06-11T13:21:54Z
dc.date.created.spa.fl_str_mv 2020
dc.type.eng.fl_str_mv article
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dc.identifier.issn.none.fl_str_mv 1663-9812
dc.identifier.uri.none.fl_str_mv https://repository.urosario.edu.co/handle/10336/24946
url https://doi.org/10.3389/fphar.2020.00555
https://repository.urosario.edu.co/handle/10336/24946
identifier_str_mv 1663-9812
dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.citationEndPage.none.fl_str_mv 555
dc.relation.citationStartPage.none.fl_str_mv 555
dc.relation.citationTitle.none.fl_str_mv Frontiers in pharmacology
dc.relation.citationVolume.none.fl_str_mv Vol. 11
dc.relation.ispartof.spa.fl_str_mv Frontiers in pharmacology, ISSN:1663-9812, Vol.11, (2020); pp. 555-555
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